Agents used in cardiac arrhythmias

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Agents used in cardiac arrhythmias

• Martin terba, PharmD., PhD.
• Department of Pharmacology
• Faculty of Medicine HK, Charles University

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Normal conduction within the heart
According to Katzung's Basic Clinical
Pharmacology. McGraw-Hill Medical 9 edition
(December 15, 2003)
Aorta
M /?1
SA node
VC
Atrial myocardium
?1
AV node
SA node
Bundle of His
Purk. fibre
AV node
ventricle
Bundle of His
T
ECG
P
U
QRS
Time (s)
Purkinje fibre
0.2
0.6
0.4
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NORMAL ELECTROPHYSIOLOGY OF THE HEART CELLS

• Transmembrane potential of cardiac cells is
  determined by the distribution (concentration) of
  Na, K, Ca2, Cl- inside/out the cardiac cells
• Under resting conditions the inside/out
  distribution of these ions (namely Na and K) is
  far from being balanced (homogenous)
• Resting membrane potential is -85 mV ( outside,
  - inside)
• Na out 140 mM, inside 10-15 mM
• K out 4 mM, inside 140 mM (concentration and
  electrostatic gradients are balanced)
• The base for the this inhomogeneous distribution
  of the ions (charge) is given by impermeability
  of the sarcoplasmic membrane for ions and the
  presence of pumps restoring the resting state
• Excitation of the myocardium is based on the
  selective and temporally harmonized changes in
  permeability sarcoplasmic membrane for given ions
  (the role of ion channels is crucial)

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T-Ca2 kanál
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ARRHYTHMIAS

• Electrophysiological abnormalities arising from
  the impairment of the impulse
• 1. genesis (origin), 2. conduction, 3. both
  previous
• Arrhythmias are defined by exclusion - i.e., any
  rhythm that is not a normal sinus rhythm (NSR,
  60-100 bpm) is an arrhythmia
• With respect to the
• Frequency bradyarrythmias vs. tachyarrhythmias
• Localization supraventricular (SV), ventricular
  (V)
• Mechanism early after depolarisation (EAD),
  delayed after depolarisation (DAD), re-entry
• CLASSIFICATION
• 1. Bradyarrhytmias sinus b., sick-sinus
  syndrome, AV block
• 2. Tachyarrhytmias
• a) Supraventricular (SV)
• - SV extrasystoles atrial, junction
• - atrial tachycardia, flutter, fibrillation
• - AV node re-entry tachycardia (AVNRT)

b) Ventricular - ventricular
extrasystoles - ventricular tachycardia
- flutter/fibrillation
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Normal
Re-entry
According to Katzung's Basic Clinical
Pharmacology. McGraw-Hill Medical 9 edition
(December 15, 2003)
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CAUSES OF ARRHYTHMIAS

• Myocardial damage
• Hypoxia
• Ischemia-reperfusion injury
• Myocarditis
• Cardiomyopathy
• Changes in body homeostasis
• Electrolyte imbalance e.g., hypokalemia
• Acidobazic imbalance
• Hormonal regulation impairments
• Thyreotoxicosis
• Feochromocytoma
• DRUGS!
• Virtually all antiarrhytmics possess a
  proarytmogennic efect!!!!!!
• Drug-induced LONG Q-T syndrome

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ANTIARRHYTHMIC DRUGS

• Classification
• Vaughan Williams - 4 major classes
• Sicilian Gambit more precise, well designed,
  complete, thoughtful but very complicated
• Classification according to V. Williams
• Na channel blockers.
• ?-blockers
• Action potential (AP) prolonging drugs
• Ca channel blockers
• Other drugs

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ANTIARHYTMIC AGENTS
Overview of antiarrthythmics
CLASS I (Na channels blocker)
A) Disopyramide, procainamide, quinidine B)
Lidocaine, trimecaine, mexiletine C)
Propafenone, flecainide
CLASS II (b-blockers)
Esmolol Metoprolol Propranolol
CLASS III (K channels blocker)
Amiodarone Sotalol Dofetilide Ibutilide
CLASS IV (Ca channel blocker)
Diltiazem Verapamil
Other drug
(podle Lippincotts Pharmacology, 2006)
Adenosine Digoxin
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I. Class Na CHANNELS BLOCKER

• Primarily they ? depolarization velocity (Vmax)
  in phase 0.
• use dependence effect
• 3 functional conformations of Na channels
• resting, activated a inactivated
• The effect of these drugs is aimed mainly on
  activated and inactivated Na channels
• Different effect on Vmax (relatively)
• I.A medium, I.B lowest, I.C highest
• Different effect on AP duration
• I. A. prolongation (slower repolarisation)
• I. B. - shortening
• I. C. no significant effects
• Presence of antimuscarinic and negative inotropic
  effects (as e.g. IA)

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Class I.a quinidine, procainamide, disopyramide
Class I.b mesocaine, lidocaine, mexiletine,
phenytoine Class I.c propafenon, flecainide,
encainide
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I.A Class QUINIDINE

• Relatively broad spectrum of antiarrhythmic
  effects
• Optical isomer of the quinine
• Today rather obsolete drug
• Cardiac effects
• ?AP
• ? QT interval
• negative inotropic
• parasympatholytic
• Vasodilating effect
• PK oral route, liver metabolism, t1/2 6 hod,
  CYP450 3A4
• Indications currently very limited
• Rather in past prophylaxis of the
  supraventricular (exceptionally ventricular)
  arrhythmias, pharmacological cardioversion of the
  AF

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I.A Class QUINIDINE

• Adverse effects (common and serious)
• GIT diarrhoea, nausea, vomiting (in up to 30
  of treated patients)
• CNS cinchonisms headache, vertigo,
  tinnitus, visual disturbances
• haematological - thrombocytopenia, haemolytic
  anaemia)
• skin urticaria (rash), photosensitisation
• Myalgia, arthralgia, lupus-like sy., fever,
  hepatitis
• Cardiovascular system
• Induction of ventricular tachycardia (Torsades de
  pointes)
• Decreased ventricular contractility, HF
  precipitation
• Bradycardia, heart arrest
• Interactions strong inhibitor of CYP 2D6
  (anticoagulantia)
• ContraInd. AV block, symptomatic HF, long QT,
  thrombocytopenia, gravidity and lactation

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Drugs affecting quinidine metabolism
Drugs stimulating its metabolism phenytoine rifamp
icine Barbiturates

Inactive metabolite
Quinidine
Drugs inhibiting its metabolism Ketoconazole
(podle Lippincotts Pharmacology, 2000)
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I.A Class PROCAINAMIDE

• ? antimuscarinic action
• ?? negative inotropic action
• Pharmacokinetics
• Metabolised (15-30 ) to N-acetylprocainamide
  (NAPA)
• NAPA active metabolite is excreted by kidney
  (similarly as parent. c)
• Gene polymorphism - slow acetylators decrease
  the dose (? lupus risk)
• - rapid acetylators NAPA
  cumulation TdP risk
• Indications like quinidine, rarely used, rather
  short treatment (lupus)
• Adverse and toxic effects
• Hypotension, esp. after faster i.v. infusion.
• Long QT syndrome a TdP
• Lupus-like syndrome after long treatment (gt 6
  months)
• arthralgia, arthritis, rarely also inner organs
  (pleuritis, pericarditis, pneumonia, interstitial
  nephritis).
• Syndrome disappear spontaneously after drug
  withdrawal
• Other GIT (vomiting, diarrhoea), allergy, CNS
  (depressions, hallucinations), haematological
  disturbances

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I.A Class DISOPYRAMIDE

• Similar PD as quinidine
• Negative inotropic a antimuscarinic effects are
  even more pronounced
• Metabolised in the liver
• Metabolites are responsible for antimuscarinic
  effects
• Excreted by kidney (50 as metabolites)
• Indication as in quinine
• Adverse reactions
• antimuscarinic (dry mouth, visual disturbances,
  urinary retention, glaucoma worsening)
• neg. inotropic can precipitate HF

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I.B Class MESOCAINE, LIDOCAINE, MEXILETINE

• Synthetic local anaesthetics related compound
  (mexiletine)
• PK
• ONLY i.v. administration
• After p.o. ? first pass effect (80-97 )
• Liver metabolism
• t1/2 90 min
• Indications
• Acute ventricular tachyarrhythmias after M.I. and
  in cardiac surgery
• However, should not be given routinely as a
  general prophylaxis during acute M.I. treatment.
  Risk vs. benefit!
• Ventricular arrhythmias associated with digoxin
  overdose
• Adverse reactions quite acceptable and often
  predictable with appropriate dosing
• CNS paresthesia, tremor, nausea, hearing and
  speaking disturbances
• In high doses - agitation and convulsions may
  appear (treatment - diazepam), apnoea, negative
  inotropic action and hypotension

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I.B Class PHENYTOINE

• Antiepileptic drug with cardiac effects similar
  to mesocaine
• IND supraventricular and ventricular
  tachyarrhythmias, esp. those associated with
  digoxin intoxication
• PK
• p.o. a i.v. route, saturable metabolism in the
  liver (0. order PK), potent inductor of the liver
  enzymes
• Adverse reactions
• neurological disturbations (ataxia, vertigo,
  nystagm)
• megaloblastic anaemia
• Hirsutism and gum hypertrophy,

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I.C Class PROPAFENONE

• PD besides Na blocking effects
• Weak Ca channel blocker
• weak ß-blocker
• PK metabolized to active metabolites
• Genet. polymorphism slow metabolizers may have
  even 2x higher Cmax and 3x longer T1/2
• Ind SV tachyarrhythmias (WPW, AV node re-entry
  tachycardia, paroxysmal atrial fibrillation) and
  some ventricular arrhythmias
• Adverse effects
• Cardiac AV or bundle branch blockades,
  ventricular tachyarrhythmias
• GIT Nauzea, vomiting, constipation and metallic
  taste
• CNS tremor, restlessness, headache, sleeping
  disturbances
• Flecainide, encainide

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II. Class BETA-BLOCKERS

• Pacemakers decrease the rate of the spontaneous
  firing
• prolong AV conduction
• Decrease resting membrane potential (it is more
  negative) negative bathmotropic effects
• Clinical correlates
• ? TF
• ? impulse conduction to ventricles
• ? threshold for ventricular fibrillation
• Improved prognosis of patient after M.I. (sudden
  death prevention antiarrhythmic effects)
• PK differences t1/2!
• esmolol, metoprolol, propranolol

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TRÍDA III.
(podle Lippincotts Pharmacology, 2006)
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III. Class DRUGS PROLONGING AP (K channel
blockers)

• Amiodarone
• Significantly prolongs the AP and ERP of Purkinje
  fibers and ventricular myocardium
• Complex PD
• Inhibition of K, Na and Ca2 channels,
  b1-blockade
• Indication relatively broad spectrum
• Serious ventricular tachyarrhythmias
• Hemodynamically significant atrial flutter and
  fibrillation, WPW
• PK (very specific)
• i.v. (acute), can also be given p.o. but BAV is
  quite low and can be variable (20-60)
• Liver metabolism to active metabolite
• Elimination early (3-10 days, 50 of the
  drug), second phase several weeks (acute admin.
  40 days, in Css up to 100 days)
• Interaction CYP 3A4 inhibitors/inductors (e.g.
  cimetidin a rifampicin)

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III. Class AMIODARONE

• Adverse and toxic effects
• Cardiac
• bradycardia, AV blockade
• long QT syndrome and TdP risk
• Extracardiac
• Lungh fibrosis (in a serious form in up to 1 of
  patients)
• Hepatotoxicity
• Skin deposits fotodermatitis and coloured
  sun-exposed skin (blue-grey)
• Corneal microdeposits detectable already after
  few weeks of treatment, it's mostly asymptomatic,
  but may cause blurred vision in some patients
• Optic neuropathy/neuritis (rare) may result in
  blindness
• Thyreoidal dysfunction mostly hypofuction but
  hyperfunction can also occur (mechanism?... block
  T3 to T4 conversion, large doses of I in the drug
  molecule

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III. Class SOTALOL

• III. class antiarrhythmic drug with b-blocking
  effects
• L-isomer (non selective b-blocker without ISA),
• Both D and L isomers - III. class antiarrhythmic
  drug
• Isolated D-isomer was not as efficient as
  racemate
• PROLONG AP block rapid outward K current ?
  repolarization phase is slowed i.e., prolonged,
  ? longer is also effective refractory period
  (EPR)
• IND i.v. - serious ventricular and SV
  arrhythmias
• P.o. - effective in prophylaxis of recurrent SV
  arrhythmias
• To keep the sinus rhythm after cardioversion of
  AF
• ? threshold for ventricular fibrillation,
• ? occurrence of ectopic beats
• PK relatively simple and predictable (p.o. i
  i.v.) limited risk of drug interactions
• Adverse reaction generally relatively tolerable
  drug (mostly transient)
• Riskfull is the induction of the long QT due to
  the possibility of TdP occurrence (the risk in
  approx. in 3-4 patients)
• Bradycardia, HF precipitation, hypotension,
  bronchoconstriction, sleep disturbances (KI
  severe HF, asthma..)

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III. Class

• Dofetilide
• Used in patients with persisting AF to maintain
  sinus rhythm
• Proarrhythmogenic TdP, the QT monitoring is
  essential
• Ibutilide
• Similar as dofetilide
• but indicated mainly for rapid pharmacological
  cardioversion of AF and Flutter to sinus rhythm

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IV. Class Ca CHANNEL BLOCKERS

• The effects on slow response structures (SA and
  AV nodes)
• - conduction is based on Ca
• ? depressed spontaneous depolarization of SA node
• decreased AV node conduction
• decreased ventricular response in AF and flutter
• suppress AV nodal re-entry tachyarrhythmia
• x no major impact on ventricular
  tachyarrhythmias
• Rapid response structures (the rest of the
  myocardium)
• ? Ca2 channel block (L- type) in 2nd AP phase ?
  less Ca for contraction - negative inotropic
  response

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IV. Class VERAPAMIL, DILTIAZEM

• Indication SV tachyarrhythmias (for AF
  termination or to decrease the ventricular
  response)
• Adverse reactions mostly well predictable
• AV block, negative inotropic effect can cause
  precipitate HF, BP decrease
• In patients with AF coupled with sustained
  ventricular tachycardia verapamil i.v. can
  cause hemodynamic collapse
• extracardiac constipation, headache, vertigo
• Contraind hypotension, AV block of higher
  degree, WPW syndrome, HF
• Interaction do not combine with beta-blockers
  (i.v.) risk of AV blocks and cardiac arrest or
  acute HF

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Some adverse effects of Ca channels blockers
(podle Lippincotts Pharmacology, 2006)
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OTHERS

• Cardioglycosides (digoxin)
• negative dromotropic and chronotropic effect
  due to the central stimulation of the n. vagus
• ? markedly slowed AV conduction
• important for control of the ventricular response
  in AF and flutter
• Indication atrial fibrillation and flutter
  esp. When rapid ventricular response is
  associated with HF symptoms
• Mg, K
• Indication digoxin-induced tachyarrhythmias and
  Torsades de pointes (TdP)

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OTHERS

• Adenosine (endogenous purin nucleotide)
• blocks A1 receptors
• the most significant effect is on slow response
  structures
• SA and AV node inhibition of the Ca current
• ? decreased SA node firing and mainly AV
  conductivity
• i.v. only
• PK extremely short t1/2 lt 10 s
• Indication rapid and effective management of AV
  nodal re-entry tachycardia (successful in 90-95)
• Adverse reactions flush, headache, dyspnoea
  (bronchoconstriction), chest pain, palpitations,
  very rare is induction of ventricular
  fibrillation
• Drugs in bradyarrthytmias
• antimuscarinic
• beta-sympathomimetics

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NOTES TO PHARMACOTHERAPY OF ARRYTHMIAS

• Generally limited options in bradyarrhythmias
  (acute atropine, ipratropium), esp. in chronic
  forms
• The approach to antiarrhythmic treatment has
  changed a LOT in recent years evidence based
  medicine !
• Aggressive treatment aimed on complete correction
  of ECG abnormalities back to normal is not
  accepted any more as a reasonable treatment
  end-point
• The elder drugs with known risks and without
  clear proof of efficacy are being abandoned
• The enormous development in the field of
  non-pharmacological treatment changes the point
  of view
• Direct current cardioversion, Implantable
  cardioverter-defibrilator, catheterisational
  radiofrequency ablation, modern approaches of
  cardiac surgery